BPH. Prostate Neoplasia and Treatment Modalities
There are three significant diseases of the prostate: benign prostate hyperplasia (BPH), prostate cancer, and rostatitis. The costs of these three diseases are immense. In 1985, the annual treatment of prostate diseases in the US required 4.4 million physician visits, 836,000 hospitalizations, and cost over $3 billion. In 1985, the costs for BPH, prostate cancer, and prostatitis were $1.82, $0.97, and $0.29 billion respectively. clearly these diseases represent a significant percentage of the American health care dollar. In addition prostate cancer caused 39,215 deaths. BPH and prostate cancer are diseases of men over 50. Due to the aging US population, the incidence of BPH and prostate cancer will increase 50% in the next 15 years.
BPH causes urinary obstruction resulting in urinary incontinence. It occurs in almost 80% of men by the age of 80. Unregulated dihydrotestosterone is believed to cause hyperplastic prostate growth in aging men.
Pharmacotherapy for the treatment of BPH is currently aimed to relax prostate smooth muscle (alpha blockade) and decrease prostate volume (androgen suppression). Phase III clinical trials are underway evaluating selective alpha.sub.1 blockers, anti-androgens, and 5-alpha reductase inhibitors for the treatment of BPH. The most promising of these is finasteride. It has shown an ability to cause regression of the hyperplastic prostate gland in a majority of patients (Mocellini et.al. (1993) Prostate 22:291).
BPH is treated surgically with a transurethral resection of the prostate (TURP). This procedure is most common: 500,000 TURPs are performed in the US each year and 25% of men will require surgery at some time in their lives to alleviate urinary obstruction. This makes BPH the second most common cause of surgery in males after cataract surgery. The TURP procedure requires several days hospitalization as well as the surgery itself. The average medical reimbursement cost of a TURP in 1987 dollars was $8,000; in 1993 dollars this is $14,000. Unfortunately, a side-effect of the TURP is the elimination of the ejaculatory ducts resulting in impotence in 90% of patients. A TURP is prefaced by an outpatient biopsy procedure to determine if the enlargement of the prostate is benign or cancerous.
Prostate cancer is the second most common cause of cancer death in American males where only lung cancer is greater. Prostate cancer is a latent disease; many men carry prostate cancer cells without overt signs of disease. Autopsies of individuals dying of other causes show prostate cancer cells in 30% of men at age 50; by the age of 80 years, the prevalence is 60% of prostates. Further, prostate cancer can take up to 10 years to kill the patient after initial diagnosis. Prostate cancer is newly diagnosed in slightly over 100,000 men in the US. each year of which over 40,000 will die of the disease. There is also high morbidity. Cancer metastasis to bone (late stage) is common and often associated with uncontrollable pain. Metastasis also occurs to lymph nodes (early stage).
The progression of the disease is from a well-defined mass within the prostate, to a breakdown and invasion of the lateral margins of the prostate, to metastasis to regional lymph nodes, to metastasis to the bone marrow. The aggressiveness of prostate tumors varies widely. Some tumors are relatively aggressive, doubling every six months, whereas other are extremely slow-growing, doubling once every five years. As a consequence of the slow growth rate, few cancer cells are actively dividing at any one time. As a result, prostate cancer is generally resistant to radiation and chemotherapy, although both therapeutic modalities are widely used. Surgery is the mainstay of treatment but it too is largely ineffective and also removes the ejaculatory ducts, resulting in impotence.
Unfortunately, in 80% of cases, diagnosis of prostate cancer is established when the disease has already metastasized to the bones. Of special interest is the observation that prostate cancers frequently grow more rapidly in sites of metastasis than within the prostate itself, the site of the primary cancer.
The diagnosis and management of prostate cancer has become simplified with the use of measurement of serum levels of prostate-specific antigen. Prostate-specific antigen (PSA) is a protease involved in the breakdown of the ejaculate coagulum. Serum levels of PSA vary from 2-4 ng/ml and usually a single determination of an individual's PSA level is meaningless. Most frequently PSA levels are elevated in both prostate cancer and BPH. A serum PSA level of over 4 ng/ml usually warrants further investigation. Even more telling are rapid increases in serum PSA levels which can indicate active prostate cancer. A rapid rise in PSA levels from 2-4 ng/ml to over 10 ng/ml indicates active disease (Hamdy, F.C., et al. (1992) Br. J. Urol. 69:392). In end-stage metastatic disease, PSA levels can reach 200 ng/ml. PSA is a single amino acid chain of 240 AA and has been cloned (Lundwall A. and Lilja H. (1987) FEBS Lett 214:317: Lundwall A (1989) Biochem. Biophys. Res. Comm. 161:1151; Riegman et al. (1989) Biochem. Biophys. Res. Comm. 159:95).
For the treatment of prostate cancer oral estrogens and luteinizing releasing hormone analogs are used as well as surgical removal of glands that produce androgens (orchiectomy or adrenalectomy). The Nobel prize was awarded in 1966 to Charles Huggins for utilizing castration for treatment of prostate cancer. Many patients showed marked improvement after castration, but this was only temporary relief. Most of these cancers soon relapsed and presented as a therapeutically resistant form that ultimately caused death. Current therapeutic techniques use chemical forms of medical castration by shutting down androgen production in the testes, or directly block androgen production in the prostate.
Estrogens are no longer recommended for therapy because of serious, even lethal, cardiovascular complications. Luteinizing hormone releasing hormone (LHRH) analogs are used instead. LHRH analogs are equally effective when compared to estrogens, or orchiectomy. LHRH treatments are reversible, do not involve surgery, and do not impact the patient psychologically. Thus, this treatment is preferable for producing androgenic deprivation. LHRH analogs initially increase pituitary LH secretion with a subsequent increase in serum testosterone. This results in a disease "flare" that rapidly subsides as the initial increase in LHRH-mediated LH secretion is reversed when over stimulation of pituitary LHRH receptors leads to a shutdown in their function and a consequent fall in LH secretion, and thus, testicular testosterone production (Redding et al. (1982) Proc. Natl. Acad. Sci. 79:1273). However, hormonal therapy invariably fails with time with the development of hormone-resistant tumor cells. It is not known whether these cells develop as a mutation of the original hormone sensitive cells, or as a separate class of cells. However, since 20% of patients fail to respond to hormonal therapy, it is believed that hormone-resistant cells are present at the onset of therapy.
Estramustine, a steroidal nitrogen mustard derivative, is undergoing clinical trials for advanced stage prostate cancer. Estramustine was originally thought to be suitable for targeted drug delivery through conjugation of estrogen to toxic nitrogen mustard. Surprisingly however, estramustine has no alkylating or hormonal effects. Rather, estramustine disassembles microtubles inhibiting cell division. Phase II and Phase III clinical trials over the past 15 years have been disappointing when survival is used as an endpoint.
Finasteride, a 4-aza steroid (Proscar.RTM. from Merck & Co.) inhibits 5.alpha.-reductase, the enzyme responsible for the intracellular conversion of testosterone to dihydrotestosterone in the stroma of the prostate. Since dihydrotestosterone is the most potent androgen in the prostate, its elimination causes regression of prostate cancer by as much as 40% in volume. Casodexthin.RTM. is thought to inhibit cellular uptake of testosterone by blocking androgen receptors in the nucleus. However, almost all advanced cancer prostate cells fail to respond to androgen deprivation. At this stage there is no effective cytotoxic chemotherapy for prostate cancer.
A major, indeed the overwhelming, obstacle to cancer therapy is the problem of selectivity; that is, the ability to inhibit the multiplication of tumor cells, while leaving unaffected the function of normal cells. Thus, the therapeutic ratio, or ratio of tumor cell killing to normal cell killing of traditional tumor chemotherapy, is only 1.5:1. Thus, more effective treatment methods and pharmaceutical compositions for therapy and prophylaxis of prostatic hyperplasia and neoplasia are needed.